563 Distinct effects of proteasome inhibition by a novel inhibitor in lymphoid cells
Claudia P. MillerMelanie DujkaSergio RuizSaskia NeuteboomMichael A. PalladinoDavid J. McConkeyJoya Chandra
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The proteasome is the proteolytically active core of the ubiquitin-proteasome system, which regulates vital processes and which can cause various diseases when it malfunctions. Therefore, the proteasome has become an attractive target for pharmaceutical interventions. Inhibition of the cardiac proteasome by specific proteasome inhibitors has been shown to attenuate cardiac hypertrophy and ischaemia reperfusion injury of the heart. We have resolved the cardiac proteasome into its subtypes and have addressed the key question of how proteasome inhibitors affect single cardiac proteasomal subtypes. The 20S proteasome from rat heart was dissected into three different subpopulations (groups I–III), each comprising 4–7 different subtypes. The major group (group II) comprises standard proteasome subtypes; the two minor subpopulations (groups I and III) contain intermediate proteasome subtypes. All subtypes exhibit chymotrypsin-, trypsin-, and caspase-like activity but to different degrees. We have tested the effect of two common proteasome inhibitors on the chymotrypsin-like activity of all subtypes: 20–30 nmol/L MG132 caused 50% inhibition of all subtypes from groups I and II, whereas 100 nmol/L was necessary to affect group III subtypes to the same extent. However, another inhibitor, bortezomib (VELCADE™), already used clinically, inhibited 50% of the activity of group III proteasome subtypes even below 20 nmol/L, a concentration showing almost no effect on group I and II proteasome subtypes. The caspase-like activity of group II proteasome subtypes was not affected by MG132 and was inhibited by bortezomib only at concentrations above 100 nmol/L. These data show that different inhibitors have differential inhibitory effects on the various cardiac proteasome subtypes. Different cardiac subtypes are inhibited by the same dose of proteasome inhibitor to a different extent.
MG132
Proteolysis
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Objective: To explore the effects of proteasome inhibitor on dopaminergic neuron at different concentration and its possible underlying reason. Methods: SH-SY5Y cells treated with 50uM 6-OHDA were used as a toxin insulted cell model. Proteasome inhibitor lactacystin were added to the medium simultaneously at different concentrations. Cell count and SRB was used to assess cell viability. The parallel groups were used to perform proteasome activity assay. PD98059,a specific MEK1/2 inhibitor,were used to demonstrate whether or not proteasome inhibitor protects dopaminergic neuron through MAPK pathway. Results: Cell viability increased when the concentration of proteasome inhibitor were 0.1,0.25,0.5uM with the proteasome activity 83 %,75 %,64 %respectively,While cell viability decreased when the concentration of proteasome inhibitor were2,5uM with the proteasome activity24.12 %,12.6 % respectively. When PD98059 were administrated the protective effect of proteasome inhibitor was blocked. Conclusion: Proteasome inhibitor protects dopaminergic neuron at a relatively low concentration,and it is toxic to dopaminergic neuron at a relatively high concentration. The double effects of proteasome inhibitor may be related to the degree of proteasome inhibition. proteasome inhibitor protect dopaminergic neuron through MAPK pathway.
Lactacystin
Viability assay
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Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion ofbone marrow plasmacytes.It accounts for 10 ％ of all hematological malignancies.The proteasome,an intracellular enzyme complex that degrades ubiquitin-tagged proteins to regulate protein levels within the cell,plays an important role in maintaining cellular homeostasis.Proteasome inhibitors proved to be significantly effective in the clinical treatment of MM.In recent years,the application of the proteasome inhibitor has led to increased survival rates in MM patients.Bortezomib is the first proteasome inhibitor that has been approved by the US Food and Drug Administration due to its ability to reversibly inhibit the 26 s proteasome functions.Despite the fact that Bortezomib improves medical treatment,many patients experience difficulty responding to this drug and some patients who do respond eventually relapse.These results have led researchers to investigate new proteasome inhibitors with mechanisms different from those of Bortezomib.Some drugs that bind to the active site of the proteasome and irreversibly inhibit the complex have recently been developed and are currently being tested in advanced clinical trials.Here,we will elaborate on the proteasome inhibitors targeting MM and focus on newly discovered inhibitors that may overcome the resistance to Bortezomib.
Key words:
Mutiple myeloma; Proteasome inhibitor; Drug resistance
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Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors. Keywords: Proteasome inhibitor, natural product, macrocycle, argyrin, syringolin, syrbactin, rational drug design, TMC-95A, anticancer agent, medicinal chemistry, glidobactin
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Natural product
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Insights into proteasome inhibition Proteasomes are large protein complexes that degrade and remove proteins to maintain proper cellular physiology and growth. Proteasomes are a validated target for anticancer therapy, but drug design has been hampered by poor understanding of how inhibitors interact with the active site. Schrader et al. succeeded in crystallizing various proteasome-inhibitor complexes. They subsequently obtained crystal structures for the native human proteasome and eight different inhibitor complexes at resolutions between 1.9 and 2.1 Å. The inhibitors sampled include drugs that are approved or in trial for cancer treatment. Science , this issue p. 594
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In most neurodegenerative diseases, such as Parkinson's disease or Alzheimer disease, it has been reported that mechanisms of neuronal loss are involved in the proteasomal dysfunction due to the abnormal intracellular accumulation of proteins. Namely, in neurodegenerative disease, an accumulation of aberrant proteins load to proteasome with burden to cause neuronal death. It suggests that the means that activate proteasome function may become a potential therapy for neurodegenerative disease. We try to investigate the means activity proteasome function to search for therapies for neurodegenerative disease. Exposure to proteasome inhibitor showed toxicity with most cells, including a nerve cell, but sub–toxic exposure to proteasome inhibitors reduced neuronal death caused by subsequent exposure to the high dose of proteasome inhibitors. We name it proteasome tolerance. We hypothesize that proteasome tolerance is induced by some genes. We use Affymetrix Human Genome U133 Plus 2.0 Array to investigate global gene expression changes of SH–SY5Y treated with proteasome inhibitor Lactacystin or Epoxomicin for 1–8 hour to gain proteasome tolerance. The expression of the genes causing “proteasome tolerance” may be the key for therapy for neurodegenerative disease.
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Highly regulated intracellular proteolysis is necessary for cell-cycle progression and cell division. The ubiquitin–proteasome pathway (UPP) plays a central role in the degradation of proteins and has therefore become an important, novel therapeutic target for diseases involving cell proliferation, most notably cancer. Proteasome inhibitors were initially used as research tools in cell biology to characterise the properties of the UPP. It was later determined that proteasome inhibition induced cell-cycle arrest and programmed cell death (apoptosis) in cancer cells in vitro and could inhibit tumour growth in animal xenograft models. Several classes of molecules that have proteasome-inhibiting characteristics have been studied. The dipeptidyl boronic acid bortezomib (Velcade™ Millennium Pharmaceuticals, Inc.), formerly known as PS-341, LDP-341 and MLN-341, is a potent and specific inhibitor of the proteasome that holds promise as a potential human therapeutic. It is the first proteasome inhibitor to be examined in human clinical trials and according to preliminary Phase I and II data, the drug has exhibited both manageable toxicities and biological activity.
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The observation that tumour cells are more sensitive to pharmacological inhibition of the proteasome than normal cells has led to the development of the proteasome inhibitor bortezomib. To date, this is the only proteasome inhibitor that has been approved for clinical use. The clinical success of bortezomib, combined with the occurrence of adverse effects and the development of clinical resistance against this compound, has initiated the development of a broad range of second-generation proteasome inhibitors as well as of assays that can be used to establish a relationship between the extent and type of proteasome inhibition and the effectiveness of a particular drug. In the present paper, we discuss new strategies that may be used in the future to overcome drug resistance and to broaden the use of proteasome inhibitors for the treatment of both cancer and infectious and autoimmune disease.
Drug Development
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Probing the Specificity and Activity Profiles of the Proteasome Inhibitors Bortezomib and Delanzomib
The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib.
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氧化应力，由长期的乙醇消费产生了，是 hepatotoxicity 和肝损害的一个主要原因。由于乙醇，由 CYP2E1 的新陈代谢主要是的导出氧的自由激进分子的增加的生产在细胞质并且在线粒体定位了，它做不仅伤害肝房间，而且另外的重要机关，例如心和大脑。因此，有需要让更好的处理提高抗氧化剂反应元素。迄今为止，没有确定的治疗在含酒精的病人的肝稀释氧化应力的高水平。堵住这个氧化压力， proteasome 禁止者治疗被发现了显著地提高暴露于乙醇的 hepatocytes 的抗氧化剂反应元素。最近的研究在 cytoprotective 对导致乙醇的氧化应力和肝脂肪变性完成的在低剂量的 proteasome 禁止者治疗有的含酒精的肝疾病的一个试验性的模型出现了。因为，对氧化应力的 proteasome 禁止者治疗的有益的效果发生了抗氧化剂反应元素(谷胱甘肽 peroxidase 2， superoxide dismutase 2，谷胱甘肽合成酶，谷胱甘肽 reductase，和 GCLC ) 当老鼠喂了酒精时，是起来调整的与 PS-341 的低剂量被对待(Bortezomib， Velcade ?) 。因为，这是重要发现 proteasome 禁止者治疗再循环酶的起来调整的反应的氧种类移动和谷胱甘肽，当乙醇喂时独自下面调整这些抗氧化剂元素。第一次，由一个高度特定、可逆的禁止者的 proteasome 抑制与长期的乙醇喂导致 proteasome 抑制不同，这被显示出。当以前由我们的组出现，喂的长期的乙醇在 ubiquitin proteasome 小径引起一个复杂机能障碍，它影响 proteasome 系统，以及 ubiquitination 系统。在含酒精的肝疾病的 proteasome 禁止者治疗的有益的效果与 proteasome 禁止者可逆性和 proteasome 活动 72 h 柱子 PS-341 管理的反弹有关。
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